Alcoholism is a substantial medical and social problem in the U.S. and relapse represents a major[unreadable] challenge to treatment efforts. Currently, there is no therapeutic intervention that is fully satisfactory in[unreadable] preventing relapse and sustaining abstinence. While dependence is known to contribute to the problem of[unreadable] relapse, this issue has not been thoroughly studied. The focus and overall objective of this proposal is to[unreadable] utilize a mouse model of EtOH dependence and relapse to evaluate the ability of pharmacotherapies to[unreadable] reduce voluntary EtOH drinking, as well as neurochemical alterations that may underlie motivation to[unreadable] drink in dependent compared to non-dependent animals. A contemporary view of alcohol and drug[unreadable] addiction indicates that activation of different neurochemical systems within the brain reward ("motive")[unreadable] circuitry play a critical role in establishing the initial reinforcing effects of EtOH, as well as shaping[unreadable] motivational forces that perpetuate EtOH use/abuse during later stages in addiction. The mesolimbic[unreadable] dopamine pathway, with the nucleus accumbens being a key target structure, is a prominent component[unreadable] of this circuitry. Among several neurotransmitter systems that impinge on this dopamine pathway,[unreadable] glutamate transmission has emerged as a key player in contributing to the motivational effects of EtOH. A[unreadable] guiding principle of this proposal is that activation of the mesolimbic dopamine pathway plays an important[unreadable] role in establishing the acute reinforcing properties of EtOH, while adaptive changes in dopamine and[unreadable] glutamate transmission contribute to conditions that promote relapse and engender excessive EtOH[unreadable] drinking behavior characteristic of dependence. The research plan entails use of in vivo microdialysis[unreadable] procedures to characterize changes in extracellular levels of dopamine and glutamate in nucleus[unreadable] accumbens associated with voluntary EtOH drinking, as well as evaluation of various pharmacological[unreadable] agents for their ability to influence concomitant measures of behavior (drinking) and associated[unreadable] neurochemical changes in the model of dependence and relapse. The overall goal of the proposal is to[unreadable] provide new information about neural substrates underlying EtOH drinking in dependent compared to nondependent[unreadable] subjects, as well as evaluate the ability of potential pharmacotherapeutics to impact both[unreadable] neurochemical and behavioral (drinking) changes related to dependence and relapse.[unreadable]